Nitrosamines, like other groups of chemical carcinogens, require metabolic activation to render them toxic. The activation process is mediated by enzymes and involves, at least in some cases,
hydroxylation of the a-carbon. Figure 11.6 shows
the hypothesized formation mechanisms of an
alkylating agent from nitrosamines.
The nitrosamines exhibit a good deal of
organ specificity in their carcinogenic effect. For example, DMN is an active
liver carcinogen with some activity in the kidney,
and benzylmethylnitrosamine is specific for the
esophagus. The carcinogenic activity of many nitrosamines has been examined. In over 100 food substances assayed so far, approximately 80% were shown to be carcinogenic in at least one animal species. In fact, DEN is active in 20 animal species. As a result, DMN and DEN are two of the most potent carcinogens in this group. Administration of DMN at 50 ppm in the diet produces malignant liver tumors in rats in 26 to 40 weeks. Higher doses of DMN were shown to produce kidney tumors. In administration of DEN, when dosage is reduced below 0.5 mg/kg, a subsequent lag period between dosing and onset of tumors is shown to increase, with the total tumor yield remaining roughly the same. Alternatively, with a lower dose of 0.3 mg/kg, the lag time is 500 days, and finally, for a dose of 0.075 mg/kg, the lag time is increased to 830 days. No clear threshold dose for carcinogenicity of nitrosamines in the diet has been established yet.
